During learning and memory synaptic connections between neurons get bigger and stronger through local synthesis of specific synaptic proteins encoded by RNAs that are transported to active synapses in the form of trafficking intermediates called RNA granules. This proposal focuses on three aspects of RNA granule assembly - segregation, linkage and function. Segregation refers to the mechanism whereby certain RNA molecules are segregated into granules that are targeted to dendrites while other RNAs are segregated into granules that are retained in the perikaryon. We will determine if specific RNA bdining proteins are sufficient to ensure differential segregation. Linkage refers to the mechanism whereby multiple different RNA molecules are co-assembled or linked together in the same granule. We will determine if scaffold proteins link multiple RNA molecules together in one granule. Function refers to the role of RNA granule assembly in learning and memory. We will determine if knocking out specific granule compoents in the hippocampus affects learning and memory in transgenic mice. The specific aims of this proposal are: 1) measure quantitative parameters for combinatorial molecular interactions among granule components in vitro; 2) measure quantitative parameters for combinatorial molecular interactions among granle components in hippocampal neurons; 3) simulate RNA granule assembly using rule based modeling in silico; 4) knockout specific granule components in hippocampal neurons and analyze effects on learning and memory. Since RNA granules are required for synaptic plasticity associated with learning and memory, understanding RNA granule assembly is essential for understanding learning and memory. Using RNA granules to deliver RNAs encoding novel proteins to the synapse may provide a way to transform the synapse to improve long term memory and to treat diseases that affect the synapse.